Excipients: Sucrose 25.2mg in each XL 120mg capsule. Sucrose 37.8mg in each XL 180mg capsule. Sucrose 50.4mg in each XL 240mg capsule.

Transcription

1 1. NAME OF THE MEDICINAL PRODUCT Dilzem XL 120mg Prolonged-release Hard Capsules Dilzem XL 180mg Prolonged-release Hard Capsules Dilzem XL 240mg Prolonged-release Hard Capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each Dilzem XL 120mg capsule contains diltiazem hydrochloride 120mg. Each Dilzem XL 180mg capsule contains diltiazem hydrochloride 180mg. Each Dilzem XL 240mg capsule contains diltiazem hydrochloride 240mg. Excipients: Sucrose 25.2mg in each XL 120mg capsule. Sucrose 37.8mg in each XL 180mg capsule. Sucrose 50.4mg in each XL 240mg capsule. For full list of excipients, see Section PHARMACEUTICAL FORM Prolonged-release capsule, hard. White, hard gelatin capsules, printed with e120 and containing roughly spherical white to off-white beads. White, hard gelatin capsules, printed with e180 and containing roughly spherical white to off-white beads. White, hard gelatin capsules, printed with e240 and containing roughly spherical white to off-white beads. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prophylaxis and treatment of angina pectoris. Treatment of mild to moderate hypertension. 4.2 Posology and method of administration Oral use only. Adults: annotated for Change of Ownership Page 1 of 11

2 Hypertension: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required. Angina Pectoris: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required. Elderly patients and those with renal or hepatic impairment: Dosage should commence at the lower level of 120mg once daily and be increased slowly. Do not increase the dose if the heart rate falls below 50 beats per minute. Children: This product is not recommended for use in children. 4.3 Contraindications - Use in women of child-bearing potential - Concomitant administration of dantrolene infusion due to the risk of ventricular fibrillation - Shock - Acute cardiac infarct with complications (bradycardia, severe hypotension, left heart insufficiency) - Bradycardia (pulse rate, at rest, of less than 50 bpm), hypotension (less than 90 mm Hg systole), second or third degree heart block or sick sinus syndrome, except in the presence of a functioning ventricular pacemaker - Atrial fibrillation/flutter and simultaneous presence of a WPW (Wolff-Parkinson- White) syndrome (increased risk of triggering a ventricular tachycardia) - Manifest myocardial insufficiency - Left ventricular failure with stasis - Hypersensitivity to diltiazem or any of the excipients 4.4 Special warnings and precautions for use - Capsules should not be sucked or chewed. - The use of diltiazem hydrochloride in diabetic patients may require adjustment of their control. - Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem treatment (see section 4.5). - Increase of plasma concentrations of diltiazem may be observed in the elderly and in patients with renal or hepatic insufficiency. The contraindications and precautions should be carefully observed and close monitoring, particularly of heart rate, should be carried out at the beginning of treatment. The product should be used with caution in patients with hepatic dysfunction. Abnormalities of liver function may occur during therapy. Very occasional reports of abnormal liver function have been received, these reactions have been reversible upon discontinuation of therapy. annotated for Change of Ownership Page 2 of 11

3 - First degree AV block or prolonged PR interval. Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second or third degree AV block (see section 4.5 for information concerning beta-blockers and digitalis). - Close observation is necessary in patients with reduced left ventricular function and bradycardia (risk of exacerbation) (see section 4.3). - Diltiazem is not recommended for use in patients with acute porphyria unless other safer alternatives are not available. - There have been reports of calcium-channel blockers exacerbating muscle weakness in patients with myasthenia gravis. Diltiazem should be used with caution in such patients. - Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility. Therefore it should be used with caution in patients at risk to develop an intestinal obstruction. Residues from slow release formulations of the product may pass into the patient s stools; however, this finding has no clinical relevance. - Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression. - Owing to the presence of sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals. 4.5 Interaction with other medicinal products and other forms of interaction Concomitant use contraindicated: Dantrolene (infusion): Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and dantrolene are administered concomitantly. The combination of a calcium antagonist and dantrolene is therefore potentially dangerous (see section 4.3). Concomitant use requiring caution: Anaesthetics: Anaesthetists should be warned that a patient is taking diltiazem. The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anaesthetics may be potentiated by calcium channel blockers. When used concomitantly, anaesthetics and calcium channel blockers should be titrated carefully. Statins: Due to metabolic interaction via CYP3A4, treatment with HMG CoA reductase inhibitors such as simvastatin, atorvastatin or lovastatin, in combination with diltiazem, should be started at the lowest possible dose and titrated upwards. If a patient is already taking an HMG CoA reductase inhibitor a reduction in that dose should be considered and re-titration against serum cholesterol concentrations carried out. Patient monitoring for signs and symptoms of annotated for Change of Ownership Page 3 of 11

4 rhabdomyolysis and myopathy is recommended. CYP3A4 is not involved in the metabolism of fluvastatin, pravastatin and rosuvastatin. Lithium: Risk of increase in lithium-induced neurotoxicity. Warfarin: There have been reports in the literature of diltiazem interactions with warfarin. Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects): In all the patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses. Theophylline: Increase in circulating theophylline levels. It is recommended that the plasma theophylline concentrations be assayed and that the dose should be adjusted if necessary. Alpha-antagonists: Increased antihypertensive effects: Concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem with an alpha-antagonist should be considered only with the strict monitoring of the blood pressure. Amiodarone, digoxin: Increased risk of bradycardia: Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are used. Amiodarone in combination with diltiazem may also cause AV block and myocardial depression. It is recommended that the plasma digoxin concentrations be assayed and that the dose should be adjusted if necessary. Cardiac glycosides may cause a greater degree of AV blocking, reduce the heart rate or induce a hypotensive effect. Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sinoatrial and atrio-ventricular conduction disturbances and heart failure (synergistic effect). Such a combination must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment. Other antiarrhythmic agents: Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended (additive risk of increased cardiac adverse effects). This combination should only be used under close clinical and ECG monitoring. Diuretics, ACE inhibitors or other antihypertensive agents: Patients should be carefully monitored when taking diltiazem concomitantly with these agents. Carbamazepine: Increase in circulating carbamazepine levels: It is recommended that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if necessary. Rifampicin: Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin: The patient should be carefully monitored when initiating or discontinuing rifampicin treatment. annotated for Change of Ownership Page 4 of 11

5 Anti-H2 agents (cimetidine, ranitidine): Increase in plasma diltiazem concentrations. Patients currently receiving diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-h2 agents. An adjustment in diltiazem daily dose may be necessary. Ciclosporin: Increase in circulating cyclosporin levels: It is recommended that the cyclosporin dose be reduced, renal function be monitored, circulating cyclosporin levels be assayed and that the dose should be adjusted during combined therapy and after its discontinuation. Benzodiazepines (midazolam, triazolam): Diltiazem significantly increases plasma concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short-acting benzodiazepines metabolized by the CYP3A4 pathway in patients using diltiazem. Corticosteroids (methylprednisolone): Inhibition of methylprednisolone metabolism (CYP3A4) and inhibition of P-glycoprotein: The patient should be monitored when initiating methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be necessary. General information to be taken into account: Due to the potential for additive effects, caution and careful titration are necessary in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction. Diltiazem is metabolized by CYP3A4. A moderate (less than 2 fold) increase of diltiazem plasma concentration in cases of co administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co administration with other CYP3A4 substrates may result in an increase in plasma concentration of either co administered drug. Co administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations. Simultaneous administration with enzyme inducers such as rifampicin and phenobarbital may lead to reduced activity of diltiazem. Antihypertensives: Diltiazem hydrochloride should only be administered with great care to patients receiving concurrent treatment with antihypertensives or other hypotensive agents including halogenated anaesthetics or drugs with moderate protein binding. Diltiazem hydrochloride will not protect against effects of withdrawal of ß-adrenoceptor blocking agents, nor the rebound effects seen with various antihypertensives. There may be an additive effect when diltiazem is used with drugs which may induce bradycardia or with other antihypertensives. annotated for Change of Ownership Page 5 of 11

6 4.6 Pregnancy and lactation There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity in certain animal species (rat, mice, rabbit). Diltiazem should not be used during pregnancy, as well as in women of child bearing potential not using effective contraception (see section 4.3). Diltiazem is excreted in breast milk at low concentrations. Breast feeding while taking this drug should be avoided. If use of diltiazem is considered medically essential, an alternative method of infant feeding should be instituted. 4.7 Effects on ability to drive and use machines On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the ability to drive and use machines could be altered. However, no studies have been performed. 4.8 Undesirable effects The following CIOMS frequency rating is used, when applicable: Very common ( 1/10); common ( 1/100 to <1/10); uncommon ( 1/1,000 to 1/100); rare ( 1/10,000 to 1/1,000); very rare ( 1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness. Blood and lymphatic system Psychiatric Nervous system Very common Common Uncommon Rare Not known Headache, dizziness Nervousness, insomnia Thrombocytopenia, lymphadenopathy, eosinophilia Hallucinations, mood changes (including depression), personality change Extrapyramidal syndrome, gait abnormality, syncope, amnesia, paraesthesia, somnolence, tremor annotated for Change of Ownership Page 6 of 11

7 Cardiac Vascular Gastrointestinal Very common Common Uncommon Rare Not known Atrioventricular block (may be of first, second or third degree; bundle branch block may occur), palpitations Flushing Constipation, dyspepsia, gastric pain, nausea Bradycardia Orthostatic hypotension Vomiting, diarrhea Dry mouth Sinoatrial block, congestive heart failure, arrhythmia, angina Vasculitis (including leukocytoclastic vasculitis), hypotension Gingival hyperplasia, gingivitis Hepatobiliary Skin and subcutaneous tissue Reproductive system and breast General and administration site conditions Eye Investigations Peripheral oedema Erythema Oedema, asthenia, malaise Hepatic enzymes increase (AST, ALT, LDH, ALP increase) Hepatitis Urticaria Allergic skin reactions, photosensitivity (including lichenoid keratosis at sun exposed skin areas), angioneurotic oedema, rash, erythema multiforme (including Steven-Johnson's syndrome and toxic epidermal necrolysis), sweating, exfoliative dermatitis, acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever, petechiae, pruritus Gynecomastia, sexual difficulties Amblyopia, eye irritation CK elevation, weight increase annotated for Change of Ownership Page 7 of 11

8 Respiratory, thoracic and mediastinal Metabolism and nutrition Renal and urinary Musculoskeletal and connective tissue Ear and labyrinth Very common Common Uncommon Rare Not known Dyspnoea, epistaxis, nasal congestion Anorexia, hyperglycaemia Nocturia, polyuria Osteoarticular pain, muscle pain, muscle weakness Tinnitus 4.9 Overdose The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances. Experience of overdosage in man is limited but cases of spontaneous recovery have been reported. However, it is recommended that patients with suspected overdose should be placed under observation in a coronary care unit with facilities available for treatment of any possible hypotension and conduction disturbances that may occur. Most patients suffering from overdosage of diltiazem become hypotensive within 8 hours of ingestion. With bradycardia and first to third degree atrioventricular block also developing cardiac arrest may ensue. Hyperglycaemia is also a recognised complication. The elimination half-life of diltiazem after overdosage is estimated to be about hours. If a patient presents early after overdose, gastric lavage should be performed and activated charcoal administered to reduce diltiazem absorption. Hypotension should be corrected with plasma expanders, intravenous calcium gluconate and inotropic agents (dopamine, dobutamine or isoprenaline). Symptomatic bradycardia and high grade AV block may respond to atropine, isoprenaline or occasionally cardiac pacing which may be useful if cardiac standstill occurs. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Diltiazem has pharmacologic actions similar to those of other calcium channel blocking agents such as nifedipine or verapamil. The principal physiologic action of diltiazem is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells. annotated for Change of Ownership Page 8 of 11

9 Calcium plays important roles in the excitation-contraction coupling processes of the heart and vascular smooth muscle cells and in the electrical discharge of the specialised conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium. By inhibiting calcium influx, diltiazem inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries. Dilation of systemic arteries by diltiazem results in a decrease in total peripheral resistance, a decrease in systemic blood pressure and a decrease in the afterload of the heart. The reduction in afterload, seen at rest and with exercise, and its resultant decrease in myocardial oxygen consumption are thought to be responsible for the beneficial effects of diltiazem in patients with chronic stable angina pectoris. In patients with prinzmetal variant angina, inhibition of spontaneous and ergonovine-induced coronary artery spasm by diltiazem results in increased myocardial oxygen delivery. 5.2 Pharmacokinetic properties a) General Characteristics Absorption: Capsules seem to have a similar bioavailability to tablets (30-40%), with peak concentrations for the prolonged release product after 8-11 hours compared with 1-2 hours after the conventional release product. The relatively low bioavailability is due to first pass metabolism in the liver to an active metabolite. Distribution: Diltiazem hydrochloride is lipophilic and has a high volume of distribution. Typical study results are in the range of 3-8 litres/kg. Protein binding is about 80% and is not concentration-dependent at levels likely to be found clinically. Protein binding does not appear to be influenced by phenylbutazone, warfarin, propranolol, salicylic acid or digoxin. Metabolism: Diltiazem hydrochloride is extensively metabolised in the liver. N- monodesmethyl diltiazem is the predominant metabolite followed quantitatively by the desacetyl metabolite, which has some pharmacological activity. The efficacy of the metabolites, desacetyl diltiazem and N-monodesmethyl diltiazem is 25-50% and about 20% respectively of that of diltiazem. In liver function delayed metabolism in the liver is likely. These metabolites are converted to conjugates, generally the glucuronide or the sulphate. Elimination: Diltiazem is excreted in the form of its metabolites (about 35%) and in the non-metabolised form (about 2-4%) via the kidneys while about 60% is excreted via the faeces. The average elimination half life period for diltiazem is 6-8 hours but may vary between 2 and 11 hours. Although the elimination half life is not changed after repeated oral administration, diltiazem and also the desacetyl metabolite show a slight accumulation in the plasma. b) Characteristics in Patients Decreased first-pass metabolism in the elderly tends to result in increased plasma concentrations of calcium antagonists but no major changes have been found with diltiazem. Renal impairment did not cause significant changes in diltiazem annotated for Change of Ownership Page 9 of 11

10 pharmacokinetics. Plasma concentrations of diltiazem also tend to be higher in hepatic cirrhosis due to impaired oxidative metabolism. 5.3 Preclinical safety data Chronic toxicity studies in rats revealed no remarkable changes at oral doses up to 125 mg/kg/day although there was a 60% mortality at this dose. In dogs chronically treated with oral doses of 20 mg/kg/day, transient rises in SGPT were observed. Embryotoxicity has been reported in mice, rats and rabbits following i.p. administration of diltiazem. Main types of malformations included limb and tail defects with a small number of vertebral and rib deformities also noted. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Fumaric acid Talc Povidone Sugar spheres (containing sucrose and maize starch) Ammonio methacrylate copolymer Type B Ammonio methacrylate copolymer Type A The capsule shell contains: Gelatin Titanium dioxide (E171) The printing ink contains: Shellac Black iron oxide (E172) Propylene glycol (E1520) 6.2 Incompatibilities Not applicable. 6.3 Shelf life Two years from the date of manufacture. 6.4 Special precautions for storage Do not store above 25 o C. Store in the original package in order to protect from light and moisture. 6.5 Nature and contents of container Jaysquare container, containing 7, 20, 30, 50, 60 or 100 capsules. PVC/PVDC blister pack, containing 4, 28 or 30 capsules. annotated for Change of Ownership Page 10 of 11

11 6.6 Special precautions for disposal and other handling Not applicable. 7. MARKETING AUTHORISATION HOLDER Cephalon UK Limited 1 Albany Place Hyde Way Welwyn Garden City Hertfordshire AL7 3BT 8. MARKETING AUTHORISATION NUMBER(S) Dilzem XL 120 mg PL 16260/0020 Dilzem XL 180 mg PL 16260/0021 Dilzem XL 240 mg PL 16260/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 15 April DATE OF REVISION OF THE TEXT 15 April LEGAL CATEGORY POM annotated for Change of Ownership Page 11 of 11